Diagnosis and risk factors of hippocampal sclerosis of aging; a common Alzheimer's mimic in the oldest old

老年性海马硬化的诊断及危险因素；

• 批准号: 10294794
• 负责人: Seyed Ahmad Sajjadi
• 金额: $ 40.78万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294794
• 关键词: Aged, 80 and over; Aging; Alzheimer' s Disease; Area; Atrophic; Autopsy; Biological Markers; Blood Vessels; Brain; Clinical; Cognitive; Dementia; Diagnosis; Diagnostic; Encephalopathies; Gliosis; Goals; Guidelines; Hippocampal Formation; Hippocampus (Brain); Image; Impaired cognition; Laboratories; Lead; Leadership; Life; Measures; Methods; Parents; Pathologic; Pathology; Phosphorylation; Population; Public Health; Recommendation; Research; Risk Factors; Sampling; Serology; Slide; Temporal Lobe; Work; age group; age related; base; biomarker development; hippocampal sclerosis; imaging biomarker; improved; limbic-predominant age-related TDP-43 encephalopathy; neuropathology; parent project; protein TDP-43

Abstract Hippocampal sclerosis of aging (HS) is an important degenerative pathology in the oldest old. It is present in up to a third of brain autopsy samples of those who die with dementia and has a stronger association with dementia than Alzheimer's disease neuropathology (ADNP) in this age group. Abnor- mal phosphorylation of TAR DNA binding protein of 43 kDa (TDP-43) is considered by some to be the underlying reason for HS. HS and TDP-43 proteinopathy can only be diagnosed at post-mortem as there are no available biomarkers. Currently, diagnosis of HS is dependent upon presence and de- gree of ADNP. This makes it impossible to study the relationship between these pathologies and their risk factors independently. Moreover, the increasing recognition of the relation between TDP-43 pa- thology and HS has necessitated elucidation of this relationship in the parent project. However, cur- rent national guidelines used for pathological assessment of brain samples in the parent project, only recommend a limited examination of brain for TDP-43 pathology. This might in turn lead to under- recognition of the extent of TDP-43 pathology. Given the fact that the oldest old are the fastest grow- ing segment of our population with the highest rate of dementia, there is a pressing need to improve the diagnosis of these important degenerative neuropathologies in this age group. In this supplement, we propose improving hippocampal sclerosis and TDP-43 neuropathological char- acterization by providing more detailed assessment of HS that are independent of ADNP and by ex- amining extra sections of the brain for presence of TDP-43 pathology. In Aim 1, we will examine the slides from 450 autopsied brains of the parent project to assign HS diagnosis solely based on the presence of disproportionate atrophy in HS relevant areas. We hypothesize that assigning HS diag- nosis independent of ADNP will lead to a significant increase in the number of those with HS diagno- sis. In Aim 2, We will examine an extra section of the brain from temporal lobe in 450 autopsied brains of the parent project to determine presence of abnormal TDP-43 pathology enabling more pre- cise recognition of TDP-43 pathology spread. We hypothesize determination of temporal lobe TDP-43 pathology load will lead to a significant increase in the number of cases with the most advanced stage of TDP-43 pathology. Completion of the proposed work will lead to a more robust identification of hippocampal sclerosis and its relationship to TDP-43 pathology. This is an important step towards better understanding of an important dementia related pathology in the fastest growing segment of population with highest rates of dementia.

摘要 老年性海马硬化症（hippocampus sclerosis of aging，HS）是一种重要的老年退行性病变。是 在那些死于痴呆症的人的大脑尸检样本中， 在这个年龄组中，阿尔茨海默病神经病理学（ADNP）与痴呆的相关性更高。Abnor 一些人认为TAR DNA结合蛋白43 kDa（TDP-43）的磷酸化异常是 HS的根本原因。HS和TDP-43蛋白质病只能在尸检时诊断， 没有可用的生物标志物。目前，HS的诊断取决于存在和脱- ADNP的。这使得不可能研究这些病理学与它们之间的关系。 风险因素独立。此外，越来越多的人认识到TDP-43 pa- 由于人类学和人类住区的关系，有必要在母项目中阐明这种关系。但是，狗- 仅在母项目中租用用于脑样本病理学评估的国家指南 建议对TDP-43病理学进行有限的脑部检查。这反过来可能会导致- 识别TDP-43病理学的程度。因为年纪最大的人长得最快- 在我们人口中痴呆症发病率最高的部分，迫切需要改善 在这个年龄段诊断这些重要的退行性神经病变。 在本补充中，我们建议改善海马硬化和TDP-43神经病理学特征， 通过提供独立于ADNP的更详细的HS评估和通过 检查脑组织是否存在TDP-43病变在目标1中，我们将检查 来自母项目的450个尸检大脑的幻灯片，仅根据 HS相关区域存在不成比例的萎缩。我们假设分配HS诊断- 独立于ADNP的诊断将导致HS诊断的人数显着增加， 姐在目标2中，我们将在450例尸检中检查颞叶的额外切片 父母的大脑项目，以确定异常TDP-43病理的存在，使更多的前， TDP-43病理扩散的cise识别。我们假设颞叶TDP-43 病理负荷将导致最晚期病例数量的显著增加 TDP-43的病理学 完成拟议的工作将导致更强大的识别海马硬化症 及其与TDP-43病理学的关系。这是朝着更好地理解一个 在增长最快、发病率最高的人群中， 老年痴呆症